EP2101836B1 - Implantierbares medizinprodukt mit einem pharmakologischen wirkstoff. - Google Patents
Implantierbares medizinprodukt mit einem pharmakologischen wirkstoff. Download PDFInfo
- Publication number
- EP2101836B1 EP2101836B1 EP07855068.8A EP07855068A EP2101836B1 EP 2101836 B1 EP2101836 B1 EP 2101836B1 EP 07855068 A EP07855068 A EP 07855068A EP 2101836 B1 EP2101836 B1 EP 2101836B1
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- European Patent Office
- Prior art keywords
- catheter
- active ingredient
- pharmacologically active
- elongated member
- agent
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Definitions
- This invention relates generally to medical devices and, particularly, to medical devices that are implantable either partly or completely into a human or veterinary patient.
- an implantable medical device partly or completely into the esophagus, trachea, colon, biliary tract, urinary tract, vascular system or other location with a human or veterinary patient.
- many treatments of the vascular system entail the introduction of a device such as a stent, a catheter, a balloon, a wire guide, a cannula, or the like.
- a device such as a stent, a catheter, a balloon, a wire guide, a cannula, or the like.
- the blood vessel walls can be disturbed or injured. Clot formation or thrombosis often results at the injured site, causing stenosis or occlusion of the blood vessel.
- a thrombus often forms on the device itself, again causing stenosis or occlusion.
- the patient is placed at risk of a variety of complications, including heart attack, pulmonary embolism, and stroke.
- the use of such a medical device can entail the risk of precisely the problems that its use was intended to ameliorate.
- An attempt to reduce the risk of infection is to use a pharmacologically active ingredient, such as an antibiotic, in conjunction with the catheter.
- a pharmacologically active ingredient such as an antibiotic
- Various coatings including antibiotics have been utilized in the past; however, the antibiotic typically is dispersed or dissipated from the coating in a relatively short period of time. Although effective in short-term implantation, such coatings are typically ineffective for extended duration placement such as with hemodialysis, drug infusion, or urinary tract catheters, which can be implanted in the patient for two to three years at a time.
- an implantable medical device having an outer elongated member, an inner elongated member positioned within and at least one intermediate layer positioned between the outer elongated member and the inner elongated member.
- At least one of the outer member, the inner member and the intermediate layer(s) contain channels at least partially filled with a pharmacologically active ingredient. In certain embodiments the channels form an open foam structure.
- at least one of the outer member, inner member or the intermediate layer(s) include a silicone, a polyurethane or an elastomer.
- the implantable medical device is a catheter, a urethral catheter, a catheter for suprapubic drainage, a catheter for nephrostomy drainage, a catheter for nasal pancreatic drainage or a nasal biliary drainage catheter.
- the implantable medical device is configured to allow replenishment of the pharmacologically active ingredient after partial implantation of the device in a patient.
- the pharmacologically active ingredient comprises an alpha blocker. In another embodiment, the pharmacologically active ingredient comprises a calcium channel blocker.
- the pharmacologically active ingredient comprises a thrombin inhibitor, an antithrombogenic agent, or a mixture of a thrombin inhibitor or an antithrombogenic agent.
- the pharmacologically active ingredient is an antiproliferative agent, an anti-cancer chemotherapeutic agent, an antiviral agent, an antimicrobial agent, an analgesic, an anesthetic, an antiflammatory agent or an antiencrustation compound.
- the pharmacologically active ingredient is rifampin, minocycline, or a mixture of rifampin and minocycline.
- the pharmacologically active ingredient is urokinase, streptokinase, a tissue plasminogen activator, heparin, covalent heparin, hirudin, hirulog, argatroban, D-phenylalanyl-L-poly-L-arginyl chloromethyl ketone, an antiplatelet compound or a mixture thereof.
- the pharmacologically active ingredient comprises an antimicrobial. In yet another embodiment, the pharmacologically active ingredient is bupivacaine.
- Another aspect of the present invention provides a method of preparing an implantable medical device.
- the method includes forming the implantable medical device from a material comprising at least one elastomer, forming channels in at least a portion of the elastomer and contacting at least a portion of the elastomer with a pharmacologically active ingredient under conditions wherein the pharmacologically active ingredient impregnates a least a portion of the channels.
- Yet another aspect of the present invention provides a method of delivering a pharmacologically active ingredient to a patient.
- the method includes at least partially implanting within the patient a non-metallic medical device having an outer elongated member, an inner elongated member positioned within the outer elongated member and at least one intermediate layer positioned between the outer member and the inner member. At least one of the outer member, the inner member and the at least one intermediate layer includes channels containing a pharmacologically active ingredient.
- the medical device is present within the patient for a time period sufficient to allow at least a portion of the pharmacologically active ingredient to be delivered to the patient.
- the term “implantable” refers to an ability of a medical device to be positioned, partially or wholly, at a location within a body of a human or veterinary patient for any suitable period of time, such as within a body vessel.
- the medical device may be implanted within an esophagus, trachea, colon, biliary tract, urinary tract, or vascular system of a patient.
- the terms “implantation” and “implanted” refer to the positioning of a medical device, partially or wholly, at a location within a body, such as within a body vessel.
- Implantable medical devices can be configured for transient placement within a body vessel during a medical intervention (e.g., minutes to hours), or to remain in a body vessel for a prolonged period of time after an implantation procedure (e.g., weeks or months or years). Implantable medical devices can include devices configured for bioabsorption within a body during a prolonged period of time.
- biocompatible refers to a material that is substantially non-toxic in the in vivo environment of its intended use, and that is not substantially rejected by the patient's physiological system (i.e., is non-antigenic). This can be gauged by the ability of a material to pass the biocompatibility tests set forth in International Standards Organization (ISO) Standard No. 10993 and/or the U.S. Pharmacopeia (USP) 23 and/or the U.S. Food and Drug Administration (FDA) blue book memorandum No.
- ISO International Standards Organization
- USP U.S. Pharmacopeia
- FDA U.S. Food and Drug Administration
- G95-1 entitled "Use of International Standard ISO-10993, Biological Evaluation of Medical Devices Part-1: Evaluation and Testing.”
- these tests measure a material's toxicity, infectivity, pyrogenicity, irritation potential, reactivity, hemolytic activity, carcinogenicity and/or immunogenicity.
- a biocompatible structure or material when introduced into a majority of patients, will not cause an undesirably adverse, long-lived or escalating biological reaction or response. Such a response is distinguished from a mild, transient inflammation which typically accompanies surgery or implantation of foreign objects into a living organism.
- controlled release refers to the release of a material, such as a pharmacologically active ingredient, at a predetermined rate.
- a controlled release may be characterized by a drug elution profile, which shows the measured rate that the material is removed from a material-containing device in a given solvent environment as a function of time.
- a controlled release does not preclude an initial burst release associated with the deployment of the medical device. In some embodiments of the invention an initial burst, followed by a more gradual subsequent release, may be desirable.
- the release may be a gradient release in which the concentration of the material released varies over time or a steady state release in which the material is released in equal amounts over a certain period of time (with or without an initial burst release).
- pharmacologically active ingredient refers to any agent that produces an intended therapeutic effect on the body to treat or prevent conditions or diseases.
- a “mixture” refers to a combination of two or more ingredients in which each ingredient retains its own chemical identity and properties.
- One aspect of the present invention provides an implantable medical device having channels at least partially filled with a pharmacologically active ingredient.
- Particular medical devices especially suited for application of combination materials with channels and pharmacologically active ingredients according to this invention include stents, catheters, urinary catheters, ureteral catheters or stents, long term urinary devices, tissue bonding urinary devices, penile prostheses, vascular grafts, vascular catheter ports, wound drain tubes, hydrocephalus shunts, peritoneal catheters, pacemaker capsules, artificial urinary sphincters, small or temporary joint replacements, urinary dilators, heart valves and the like.
- the medical devices according to the present invention are preferably fixed in size, having a constant cross-section, rather than being expandable in one or more dimensions.
- examples of such devices are a double-pigtail ureteral stent and a urinary Foley catheter.
- These medical devices may have some variability in their inner diameter or outer diameter, i.e., in the sense that no device has perfect dimensional stability, and also in the sense that some parts of the device may be larger than other parts.
- Implantable medical devices having a constant cross section include urinary catheters and ureteral stents, which have a majority portion with a constant cross section that does not change upon insertion.
- FIG. 1 depicts a cross-sectioned end view of a preferred illustrative embodiment of implantable medical device 10 such as a catheter having an outer elongated member 11 with a passage extending longitudinally therein.
- the outer elongated member can be simply a first layer 11 of material.
- inner elongated member 13 Positioned concentrically and in the passage of outer elongated member 11 is inner elongated member 13 with passage 14 extending longitudinally therein.
- the inner elongated member can be simply a second layer 13 of material adjacent first layer 11.
- An intermediate layer 15 having channels 16 containing a pharmacologically active ingredient is positioned between and in communication with the outer and inner elongated members 11 and 13.
- members 11 and/or 13 can also include channels containing the same, or a different, pharmacologically active ingredient.
- the channels within intermediate layer 15 can include one pharmacologically active ingredient with a higher diffusion rate, whilst another pharmacologically active ingredient with a slower diffusion rate is nearer to the outer surface of the device, for example, within channels of outer elongated member 11.
- a configuration enables the pharmacologically active ingredients to reach the "outer surfaces" substantially simultaneously.
- the pharmacologically active ingredient contained within channels of the intermediate region 15 includes a mixture of the antimicrobial drugs minocycline and rifampin.
- the channels may include a 50:50 mixture by weight of minocycline and rifampin.
- Minocycline which has a lower diffusion rate than rifampin, is also present within outer member 11.
- the intermediate region 15 can comprise multiple layers formed between the inner and outer elongated members and one or more of such layers can include channels containing pharmacologically active ingredients.
- Devices eluting multiple pharmacologically active ingredients having differing diffusion rates are described more fully in U.S. publication number 2004/0068241 A1, published April 8, 2004 , the contents of which are incorporated by reference.
- outer elongated member 11 is approximately .125" in diameter with a wall thickness of approximately .007".
- Inner elongated member 13 has an inner diameter of approximately .062" with a wall thickness of .007".
- the pharmacologically active ingredient comprising a 50:50 mixture by weight of rifampin and minocycline is positioned within channels 16 within intermediate region 15 between the inner and outer elongated members 13 and 11.
- the thickness of the intermediate layer 15 having channels 16 containing the pharmacologically active ingredient mixture is approximately .017".
- the overall wall thickness of the catheter is approximately .031".
- the material of the outer intermediate and inner members is a silicone material having a durometer in a range of 30 to 90 on the Shore A Hardness Scale.
- a silicone material is commercially available from the NU-SIL Corporation of Carpinteria, CA.
- the device of FIG. 1 may be manufactured from materials other than a silicone and many other pharmacologically active ingredients, other than rifampin and minocycline, may be included in the channels of such a device.
- FIG. 2 depicts a second embodiment of implanted medical device 20 such as a catheter with outer elongated member 21 and inner elongated member 23 positioned in the passage of outer elongated member 21.
- An intermediate layer 25 of a base material, such as foam silicone, having a substantially open foam structure is positioned between outer and inner elongated members 21 and 23.
- FIG. 3 depicts a partial, sectional side view of another embodiment of the present invention.
- Catheter 30 includes an outer elongated member 31 and an inner elongated member 33 separated by intermediate layer 35.
- Channels 36 run through at least a portion of the intermediate layer 35.
- the channels run substantially the length of the intermediate layer 35 from a delivery point normally positioned outside the patient when the device is implanted to the required delivery site of the pharmacologically active ingredient.
- Outer elongated member 31 includes regions 38 that are substantially impermeable to the pharmacologically active ingredient and regions 37 that allow the pharmacologically active ingredient to elute from the outer surface of the device.
- FIGS. 4 and 5 illustrate other medical devices applicable for use with the present invention.
- FIG. 4 depicts a Foley catheter 40, which includes elongated element 41 for draining urine from a urinary bladder of a patient.
- the Foley catheter has a constant cross section or diameter for most of the length of elongated element 41, except for a retention balloon 43.
- Balloon 43 is placed into the patient's bladder and is then inflated using fitting 46 and inflation lumen 47.
- Urine is drained from the patient through outlet 45 and outlet fitting 44, which may be used to connect to a container, such as a drainage bag.
- Elongated element 41 may be at least partly formed of a polymer or elastomer having channels.
- FIG. 5 depicts a partial view of a ureteral stent.
- Ureteral stent 50 includes a length 51 of coiled wire 55 with spaces 52 between the coils so that urine can seep into central lumen 53.
- Coiled wire 55 is coated with one of more layers 54 having channels containing a pharmacologically active ingredient.
- layers 54 may be formed from a polymer or elastomer.
- Stent 50 may have an internal rod 56 for securing end caps 57 to the stent. End caps 57 may also be secured to the end coils by soldering, welding, or brazing, or other joining technique.
- Foley catheters or ureteral stents may contain channels that are impregnated, coated, or filled with a pharmacologically active ingredient.
- Many other medical devices may contain channels that are impregnated, coated or filled with a pharmacologically active ingredient, including but not limited to, a urethral catheter, a urethral stent, a prostatic stent, a biliary stent, a pancreatic stent, a catheter for suprapubic drainage, a catheter for nephrostomy drainage, a catheter for nasal pancreatic drainage, and a nasal biliary drainage catheter.
- the implantable medical devices of the present invention are generally composed of one or more non-metallic materials. However, in certain embodiments, such devices may include a metallic base material at least partially coated with one of more layers of non-metallic materials. In one embodiment the devices comprise a polymer, preferably a biocompatible polymer.
- the medical device includes cellulose acetate, cellulose nitrate, polyethylene teraphthalate, polyurethane, polyamide, polyester, polyorthoester, polyanhydride, polyether sulfone, polycarbonate, polypropylene, high molecular weight polyethylene, polytetrafluoroethylene, polylactic acid, polyglycolic acid, a polyanhydride, polycaprolactone, polyhydroxybutyrate valerate, silicone, poly(siloxane), or another biocompatible polymeric material, or mixtures or copolymers of these materials.
- the medical device includes a silicone or a polyurethane.
- the implantable medical devices comprise a rubber, elastomer, plastic, polyethylene, polyurethane, silicone, Gortex (polytetrafluoroethylene), DACRON ® (polyethylene terephthalate), TEFLON ® (a form of PTFE, polytetrafluoroethylene), latex, elastomer or DACRON ® sealed with gelatin, collagen or albumin.
- a pharmacologically active ingredient is present within channels formed within at least one layer of the device.
- channels can be formed in any of the intermediate layers, or the inner and/or outer members.
- the pharmacologically active ingredient may be placed within the channels before implantation, for example, during the manufacture of the device.
- the pharmacologically active ingredient can be supplied through the channels, for example, in a liquid form, after the device is positioned within the patient.
- Channels may be formed in materials for stents, catheters, balloons, wire guides, cannulae, or other medical devices intended for implantation into a human or animal body.
- the medical deice of the present invention is formed, at least partially, from a polymeric or elastomeric material, such as a polyurethane or a silicone.
- a polymeric or elastomeric material such as a polyurethane or a silicone.
- One way to form channels in such materials is to foam the material.
- the materials may be formulated to foam naturally, or they may be foamed by adding a blowing agent or a gas to the mixture.
- the foam thus formed may be open cell or closed cell foam. A large percentage of open cells is preferred to store a pharmacologically active ingredient in the medical device.
- One way of forming channels is to reticulate the base material, e.g., to physically process the material or foam to open the cells and form channels or a network of channels in the material. Alternatively, channels may be formed in the polymeric material during the molding or extrusion process.
- channels may be formed through one or more of the inner member, outer member and the intermediate layers.
- FIG. 7 depicts an example of a structure with channels 71.
- a layer 70 of the device may have a cellular structure, with cells 72 and channels 71 between the cells.
- One or more pharmacologically active ingredients may reside in the channels for elution to the patient.
- the device may also be replenished by re-supply of the active ingredients, such as by injection of the ingredient into the channels.
- the intermediate layer 15 includes channels 16 containing a pharmacologically active ingredient.
- the thickness of the layer or layers and the density of channels within the layer may be designed for holding the desired amount of active ingredient and to obtain controlled release of the ingredient over a predetermined time.
- the thickness and material of outer layer 11 may also be used to obtain controlled release of pharmacologically active ingredient.
- An additional advantage of medical devices made from multilayer materials with channels is that the active ingredients may be replenished or re-charged while the medical device remains implanted or partially implanted within the patient.
- the channels are continuous from an entry point outside the body of the patient to the required site of treatment.
- a nurse or medical professional may inject controlled additional dosages of the physiologically active ingredient or ingredients through channels in the intermediate or other layers as desired.
- the device could remain in place and continue its controlled diffusion of pharmacologically active ingredient into the patient.
- a device such as a stent or a catheter
- a pharmacologically active ingredient For instance, with a urethral or Foley catheter, only the portion of the catheter near or protruding through the urethral meatus may be required to elute an antimicrobial or anti-encrustation medicament. If a patient is being treated for cancer of the ureter, a ureteral stent eluting a pharmacologically active ingredient only in the central linear portion may be appropriate, rather than a device eluting such an ingredient from portions of the stent that will lie in the kidney or the bladder.
- Limiting the active ingredient eluting region of the implanted medical device to that portion where the ingredient is needed at least has the effect of reducing the amount of ingredient necessary for affective treatment of the patient. This may help reduce over-medicating of patients, will minimize any adverse drug reactions, and may also reduce any sensitization effects.
- Medical devices of the present invention may be manufactured such that channels communicate with the surface of the device only within those regions where it is desired that the pharmacologically active ingredient be eluted from the surface.
- only a portion of the length of a catheter may contain channels, such as an open foam structure.
- the pharmacologically active ingredient is loaded into, and elutes from, the region having channels.
- foam channels are present throughout an intermediate region but this region is partially covered by a layer that is substantially non-permeable to the pharmacologically active ingredient.
- Such an embodiment allows for replenishment of the pharmacologically active ingredient while the device is implanted while permitting delivery of the active ingredient to selected regions of the patient's body.
- a ureteral stent which contains channels, for example, an open pore structure, only in the linear portion is depicted in partial cross-section in FIG. 6 .
- Ureteral stent 60 is made from an elastomer, preferably urethane or silicone.
- the stent has a pigtail 61 a on either end, with orifices 62 for entrance and exit of urine or other fluids, such as irrigation fluid.
- stent 60 only contains channels containing a pharmacologically active ingredient in the central, linear portion 63. Consequently, only the length of the ureter into which region 63 of stent 60 is placed will be treated with a pharmacologically active ingredient.
- FIG. 6A depicts an expanded view of a portion of linear portion 63.
- one or more of outer member 64, intermediate region 63 and inner member 65 can include channels having a pharmacologically active ingredient.
- pharmacologically active ingredient includes any material that is molecularly interactive with the fluids, cells, proteins or tissues of an animal including humans to augment the diagnosis, treatment or prevention of any physiologic or pathologic condition. It is further intended that this term includes therapeutic and diagnostic agents such as, for example, drugs, vaccines, hormones, steroids, proteins, previously described agents, complexing agents, salts, chemical compounds, polymers, and the like.
- a vast range of drugs, medicaments and materials may be employed as a pharmacologically active ingredient within the channels of the device of the present invention so long as the selected ingredient can survive exposure to the conditions required to place the ingredient within the channels.
- Particularly useful in the practice of the present invention are materials which prevent or ameliorate abrupt closure and restenosis of blood vessels previously opened by stenting surgery or other procedures.
- Thrombolytics which dissolve, break up or disperse thrombi
- antithrombogenics which interfere with or prevent the formation of thrombi
- Particularly preferred thrombolytics are urokinase, streptokinase and the tissue plasminogen activators.
- Particularly preferred antithrombogenics are heparin, hirudin, and the antiplatelets.
- Urokinase is a plasminogen activating enzyme typically obtained from human kidney cell cultures. Urokinase catalyzes the conversion of plasminogen into the fibrinolytic plasmin, which breaks down fibrin thrombi.
- Heparin is a mucopolysaccharide anticoagulant typically obtained from porcine intestinal mucosa or bovine lung. Heparin acts as a thrombin inhibitor by greatly enhancing the effects of the blood's endogenous antithrombin III. Thrombin, a potent enzyme in the coagulation cascade, is key in catalyzing the formation of fibrin. Therefore, by inhibiting thrombin, heparin inhibits the formation of fibrin thrombi. Alternatively, heparin may be covalently bound to the outer layer of the implantable medical device. Thus, heparin would form the outermost layer of the implantable medical device and would not be readily degraded enzymatically, and would remain active as a thrombin inhibitor.
- an antiproliferative agent such as methotrexate will inhibit over-proliferation of smooth muscle cells and thus inhibit restenosis of the dilated segment of the blood vessel.
- the antiproliferative is desirably supplied for this purpose over a period of about four to six months.
- localized delivery of an antiproliferative agent is also useful for the treatment of a variety of malignant conditions characterized by highly vascular growth.
- the device of the present invention could be placed in the arterial supply of the tumor to provide a means of delivering a relatively high dose of the antiproliferative agent directly to the tumor.
- a vasodilator such as a calcium channel blocker or a nitrate will suppress vasospasm, which is common following angioplasty procedures.
- Vasospasm occurs as a response to injury of a blood vessel, and the tendency toward vasospasm decreases as the vessel heals. Accordingly, the vasodilator is desirably supplied over a period of about two to three weeks.
- trauma from angioplasty is not the only vessel injury which can cause vasospasm, and the device may be introduced into vessels other than the coronary arteries, such as the aorta, carotid arteries, renal arteries, iliac arteries or peripheral arteries for the prevention of vasospasm in them.
- an anti-cancer chemotherapeutic agent can be delivered by the device to a localized tumor. More particularly, the device can be placed in an artery supplying blood to the tumor or elsewhere to deliver a relatively high and prolonged dose of the agent directly to the tumor, while limiting systemic exposure and toxicity.
- the agent may be a curative, a pre-operative debulker reducing the size of the tumor, or a palliative which eases the symptoms of the disease.
- the pharmacologically active ingredient in the present invention is delivered across the device, and not by passage from an outside source through any lumen defined in the device, such as through a catheter employed for conventional chemotherapy.
- the pharmacologically active ingredient of the present invention may, of course, be released from the device into any lumen defined in the device, or to tissue in contact with the device and that the lumen may carry some other agent to be delivered through it.
- tamoxifen citrate may be applied to the tissue-exposed surface of the device for delivery to a tumor located, for example in breast tissue or the prostate.
- Dopamine or a dopamine agonist such as bromocriptine mesylate or pergolide mesylate is useful for the treatment of neurological disorders such as Parkinson's disease.
- the device could be placed in the vascular supply of the thalamic substantia nigra for this purpose, or elsewhere, localizing treatment in the thalamus.
- the pharmacologically active ingredient includes at least one of heparin, covalent heparin, or another thrombin inhibitor, hirudin, hirulog, argatroban, D-phenylalanyl-L-poly-L-arginyl chloromethyl ketone, or another antithrombogenic agent, or mixtures thereof; urokinase, streptokinase, a tissue plasminogen activator, or another thrombolytic agent, or mixtures thereof; a fibrinolytic agent; a vasospasm inhibitor; a calcium channel blocker, a nitrate, nitric oxide, a nitric oxide promoter or another vasodilator; HYTRIN ® or other antihypertensive agents; an antimicrobial agent or antibiotic; aspirin, ticlopidine, a glycoprotein IIb/IIIa
- pharmacologically active ingredients include additional drugs that are effective against urinary encrustation, in addition to heparin and other drugs listed above.
- additional anti-encrustation drugs include triclosan, silver nitrate, ofloxacin, ciproflaxin, phosphorylcholine and trimethoprim.
- antimicrobial drugs including a penicillin, a cephalosporin, a carbepenem, a beta-lactam, an antibiotic, an aminoglycoside, a macrolide, a lincosamide, a glycopeptide, a tetracyline, a chloramphenicol, a quinolone, a fucidin, a sulfonamide, a trimethoprim, a rifamycin, an oxaline, a streptogramin, a lipopeptide, a ketolide, a polyene, an azole, and an echinocandin.
- Still other useful antimicrobial drugs with which an implantable medical device may be coated include alpha-terpineol, methylisothiazolone, cetylpyridinium chloride, chloroxyleneol, hexachlorophene, chlorhexidine and other cationic biguanides, methylene chloride, iodine and iodophores, triclosan, taurinamides, nitrofurantoin, methenamine, aldehydes, azylic acid, rifampycin, silver, benzyl peroxide, alcohols, and carboxylic acids and salts, and silver sulfadiazine.
- anthracyclines such as doxorubicin or mitoxantrone
- fluoropyrimidines such as 5-fluoroacil
- podophylotoxins such as etoposide.
- the salts and the derivatives of all of these are meant to be included as examples of antimicrobial drugs.
- Gendine a mixture of chlorhexidine and Gentian Violet, is another useful antimicrobial drug.
- Anticancer drugs may be useful to patients when placed into medical devices for at least partial insertion into a patient. These include docetaxel and its derivatives, fluoro-pyrimidines including 5-fluoroacil and its derivatives, hydroxyurea, mercaptopurine, cisplatin, anthracyclines including daunorubicin and doxorubicin and their derivatives, podophylotoxins including etoposide, and mitoxantrone and its derivatives, a folic acid antagonist other than methotrexate and its derivatives, a camptothecin, and a platinum complex.
- docetaxel and its derivatives include docetaxel and its derivatives, fluoro-pyrimidines including 5-fluoroacil and its derivatives, hydroxyurea, mercaptopurine, cisplatin, anthracyclines including daunorubicin and doxorubicin and their derivatives, podophylotoxins including etoposide, and
- Alpha-blockers are drugs that block receptors in arteries and smooth muscles. The action of the alpha-blocker relaxes blood vessels and leads to an increase in blood flow and a lower blood pressure, thus helping to control blood pressure or hypertension. In the bladder neck or urinary tract, alpha-blockers also relax the walls of the tract and enhance urinary flow, especially in persons suffering from prostatic hypertrophy (an enlarged prostate gland).
- Alpha-blocker drugs include doxazosin (CARDURA ® ), alfuzosin (UROXATRAL ® ), tamsulosin (FLOMAX ® ), prazosin (MINIPRESS ® ), and terazosin (HYTRIN ® ).
- Calcium channel blockers are drugs that block the entry of calcium into muscle cells. By blocking the entry of calcium, the contraction of the heart is decreased and the arteries are dilated, reducing pressure in the arteries and making blood flow easier.
- Calcium channel blockers that may be used in medical device embodiments include nisoldipine (SULAR ® ), nifedipine (ADALAT ® , PROCARDIA ® ), nicardipine (CARDENE ® ), bepridil (VASCOR ® ), isradipine (DYNACIRC ® ), nimodipine (NIMOTOP ® ), felodipine (PLENDIL ® ), amlodipine (NORVASC ® ), diltiazem (CARDIZEM ® ), and verapamil (CALAN ® , ISOPTIN ® ).
- analgesics works by interrupting the transmission of nerve impulses, and thus preventing the sensation of pain.
- Analgesics work on the peripheral and central nervous systems to reduce the perception of pain.
- Analgesics include Aspirin, naproxen, choline, diflunisal, and salsalate.
- analgesics include non-steroidal antiflammatory agents, such as naproxen, choline, diflunisal, salsalate, fenoprofen, flurbiprofen, ketoprofen, ibuprofen, oxaprozin, diclofenac, indomethacin, sulindac, acetoaminophen, tolmetin, meloxicam, piroxicam, meclofenamate, mefanimic acid, nabumetone, etodelac, keterolac, celecoxib, valdecoxib and rofecoxib, mixtures thereof, and derivatives thereof.
- non-steroidal antiflammatory agents such as naproxen, choline, diflunisal, salsalate, fenoprofen, flurbiprofen, ketoprofen, ibuprofen, oxaprozin, diclofenac, indomethacin, sulindac,
- analgesics include opioids, synthetic drugs with narcotic properties, and narcotics such as alfentanil, buprenorphine, carfentanil, codeine, codeinone, dextropropoxyphene, dihydrocodeine, endorphin, fentanyl, hydrocodone, hydromorphone, methadone, morphine, morphinone, oxycodone, oxymorphone, pethidine, remifantanil, sulfentanil, thebaine, and tramadol, mixtures thereof, and derivatives thereof.
- opioids include opioids, synthetic drugs with narcotic properties, and narcotics such as alfentanil, buprenorphine, carfentanil, codeine, codeinone, dextropropoxyphene, dihydrocodeine, endorphin, fentanyl, hydrocodone, hydromorphone, methadone, morphine, morphinone, oxycodone, oxy
- Anesthetics which may be used as a pharmacologically active ingredient in medical devices for implantation include local anesthetics such as paracetamol, bupivacaine, prilocaine, levobupivicaine, dubucaine, ropivacaine, lidocaine, and novocaine.
- Metals especially heavy metals, and ionic compounds and salts of these metals, are known to be useful as antimicrobials even in very low amounts or concentrations. These ingredients are said to have an oligodynamic effect, and they are considered oligodynamic.
- the metals include silver, gold, zinc, copper, cerium, gallium, platinum, palladium, rhodium, iridium, ruthenium, osmium, zinc, bismuth, and others.
- Other metals with lower atomic weights also have an inhibiting or cidal effect on microorganisms in very low concentrations. These metals include aluminum, calcium, sodium, magnesium, potassium, manganese, and lithium, among others.
- metals are oligodynamic metals, and their compounds and ionic ingredients are oligodynamic ingredients.
- the metals, their compounds and ions e.g., zinc oxide, silver acetate, silver nitrate, silver chloride, silver iodide and many others, may inhibit the growth of microorganisms, such as bacteria, viruses, or fungi, or they may have cidal effects on microorganisms, such as bacteria, viruses, or fungi, in higher concentrations. Because many of these compounds and salts are soluble, they may easily be placed into solution, alone or with another physiologically active ingredient, and then absorbed into a medical device or adsorbed onto its surface.
- the anionic portion of the compound or salt is desirably selected from among, but is not limited to, the oxide, acetate, ascorbate, benzoate, bitartrate, bromide, carbonate, chloride, citrate, folate, gluconate, iodate, iodide, lactate, laurate, oxalate, palmitate, perborate, phenosulfonate, phosphate, propionate, salicylate, stearate, succinate, sulfadiazine, sulfate, sulfide, sulfonate, tartrate, thiocyanate, thioglycolate, thiosulfate, and the like. Combinations of any of these may also be used.
- Silver salts are particularly useful for their inhibiting and cidal effects on microorganisms, such as bacteria, viruses and fungi.
- Such salts include, but are not limited to, silver oxide, silver chloride, silver iodide, silver citrate, silver lactate, silver acetate, silver propionate, silver salicylate, silver bromide, silver ascorbate, silver laurel sulfate, silver phosphate, silver sulfate, silver benzoate, silver carbonate, silver sulfadiazine, silver gluconate, and combinations thereof.
- Oligodynamic ingredients as defined above, including the metals, the salts, and other compounds, may advantageously be used in combination with other physiologically active ingredients.
- the salts and compounds may be particularly useful because, having different solubilities, the appropriate salts or compounds may be selected for the desired rate of release within the patient.
- the compound or compounds with the desired inhibiting or cidal effect and the desired release may be selected in coordination with another medicament or drug for the desired effect on the patient.
- a pharmacologically active ingredient is impregnated into the channels of at least one layer of the implantable medical device.
- a pharmacologically active ingredient can be impregnated into channels formed as an open pore structure.
- U.S. Patent No. 5,624,704 which is hereby incorporated by reference in its entirety, gives several examples of non-metallic medical devices intended for endoscopic or laparoscopic implantation into a patient.
- One or more pharmacologically active ingredients such as analgesics or anesthetics, may be impregnated into channels of the devices of the present invention by using the ingredients, a solvent and a penetrating ingredient.
- such a procedure can be used to impregnate a layer including an open pore structure.
- the solvent is preferably an organic solvent and the penetrating agent is an ingredient that enables the pharmacologically active ingredient to permeate the base material or layers of the device intended for implantation and to become deposited within the channels within the device.
- the organic solvent may be any solvent that can be used to dissolve pharmacologically active ingredient, such as an antimicrobial agents.
- solvents include alcohols (e.g. methanol, ethanol), ketones (acetone, methylethylketone), ethers (tetrahydrofuran), aldehydes (formaldehyde), acetonitrile, acetic acid, methylene chloride and chloroform.
- the "penetrating agent” can be any compound that can be used to promote penetration of the ingredient into the material of the medical device. Examples of such compounds are esters (i.e. ethyl acetate, propyl acetate, butyl acetate, amyl acetate, and combinations thereof), ketones (i.e.
- alkalinizing agent can be an organic and inorganic base including sodium hydroxide, potassium hydroxide, ammonia in water (27% ammonium hydroxide), diethylamine and triethylamine.
- a "high ionic strength salt” may act both as an alkalinizing agent and as a penetrating agent. Such salts include sodium chloride, potassium chloride and ammonium acetate.
- One embodiment of the present invention is a method for impregnating a non-metallic portion of a medical device with a pharmacologically active ingredient comprising the steps of forming a pharmacologically active ingredient of an effective concentration by dissolving the ingredient in an organic solvent, adding a penetrating agent to the composition and applying the ingredient to at least a portion of medical device under conditions where the pharmacologically active ingredient permeates the material of the medical device and is positioned within channels within the device.
- Another embodiment of the present invention is a method for impregnating a non-metallic portion of a medical device with a pharmacologically active ingredient comprising the steps of forming a pharmacologically active ingredient of an effective concentration by dissolving the ingredient in an organic solvent, and applying the ingredient to at least a portion of medical device under conditions where the pharmacologically active ingredient permeates the material of the medical device and is positioned within channels within the device.
- the organic solvent is methanol or ethanol.
- the pharmacologically active ingredient is bupivacaine.
- the step of dissolving a pharmacologically active ingredient may also include the step of adding an alkalinizing agent to the composition in order to enhance the reactivity of the material of the medical device.
- the pharmacologically active ingredient is heated to a temperature between about 30°C and 70°C prior to applying the composition to the medical device to increase the adherence of the pharmacologically active ingredient to the medical device material.
- the impregnated device is preferably rinsed with a liquid and milked to remove excess granular deposits and ensure uniform color of the impregnated device.
- the pharmacologically active ingredient may be applied to the medical device by dipping the implant into a solution of the dissolved ingredient for a period of between 15 and 120 minutes, and then removing the impregnated implant from the solution.
- the device is dipped in the composition for a period of approximately 60 minutes.
- the method of the present invention preferably comprises a single step of applying a pharmacologically active ingredient to the medical device.
- a pharmacologically active ingredient to the medical device.
- a preferred embodiment of the method for impregnating a catheter with a pharmacologically active ingredient that is an antimicrobial agent comprises the steps of (1) forming a pharmacologically active ingredient of an effective concentration to inhibit the growth of bacterial, viral, and or organisms, such as staphylococci, other gram-positive bacteria, gram-negative bacilli and Candida, by (a) dissolving a pharmacologically active ingredient in an organic solvent, (b) optionally adding a penetrating agent to the pharmacologically active ingredient and organic solvent composition, (c) optionally adding an alkalinizing agent to the composition to improve the reactivity of the material of the medical device; (2) heating the composition to a temperature of between about 30°C and 70°C to enhance the adherence of the pharmacologically active ingredient to the material of the medical device; (3) applying the pharmacologically active ingredient to the medical device, preferably by dipping the device in the composition for a period of about 60 minutes and under conditions where the pharmacologically active ingredient
- Another aspect of the present invention provides for a method of administrating a pharmacologically active ingredient to treat a human or veterinary patient.
- the method comprises implanting a medical device of the present invention into the body of the patient.
- a medical device of the present invention contains channels including at least one of the pharmacologically active ingredients mentioned above.
- the implantable medical device is a urethral or ureteral catheter or stent, for example, a Foley catheter introduced into the patient's bladder via the urethra for the drainage of urine.
- an antimicrobial agent such as chlorhexidine
- an anesthetic agent such as bupivacaine, may be incorporated into the device to reduce or eliminate pain associated with the placement of the device.
- an antithrombogenic agent may be included with the channels to prevent the formation of thrombi.
- other pharmacologically active ingredients including, but not limited to, those described above may be included within the channels or the device to treat or prevent a wide range of physiologic or pathologic conditions.
- two or more pharmacologically active ingredients are incorporated into the device, either within the same region of the device or within separate regions, allowing for the treatment of multiple conditions. For example, one pharmacologically active ingredient is incorporated within the inner region and another pharmacologically active ingredient is incorporated within the outer region.
- implantable medical device is merely an illustrative embodiment of the principles of this invention, and that other devices and methods for using them may be devised by those skilled in the art, without departing from the spirit and scope of the invention. It is to be understood that the invention is directed to embodiments both comprising and consisting of the disclosed parts. It is contemplated that only parts of the device can include the pharmacologically active ingredient. Furthermore, different parts of the device can include different pharmacologically active ingredients. It is also contemplated that different sides or regions of the same part of the device can include different pharmacologically active ingredients or layers. Accordingly, the invention should be limited only by the spirit and scope of the claims.
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Claims (14)
- Katheter, umfassend:ein langgestrecktes Außenelement;ein langgestrecktes Innenelement, das in dem langgestreckten Außenelement angeordnet ist; undmindestens eine Zwischenschicht, die zwischen dem langgestreckten Außenelement und dem langgestreckten Innenelement angeordnet ist, worin die mindestens eine Zwischenschicht eine offene Schaumstruktur mit einem pharmakologischen Wirkstoff umfasst,worin das langgestreckte Außenelement mindestens eine Region, die für den pharmakologischen Wirkstoff undurchlässig ist, und mindestens eine Region umfasst,die Elution des pharmakologischen Wirkstoffs der Zwischenschicht von einer Außenseite der Vorrichtung gestattet, undworin sich die Schaumstruktur von einem außerhalb des Patienten gelegenen Abgabepunkt entlang einer Länge der Zwischenschicht erstreckt und ein Nachfüllen des pharmakologischen Wirkstoffs, während der Katheter implantiert ist.
- Katheter nach Anspruch 1, worin zumindest das langgestreckte Außenelement, das langgestreckte Innenelement und/oder die mindestens eine Zwischenschicht ein Material umfasst, das aus der aus einem Silikon und einem Polyurethan bestehenden Gruppe ausgewählt ist.
- Katheter nach Anspruch 1, worin die Zwischenschicht ein Silikon oder ein Polyurethan mit einer Schaumstruktur umfasst.
- Katheter nach Anspruch 1, worin zumindest das langgestreckte Außenelement, das langgestreckte Innenelement und/oder die Zwischenschicht ein Elastomer umfasst.
- Katheter nach Anspruch 1, worin der Katheter aus der aus einem Harnröhrenkatheter, einem Katheter zur suprapubischen Drainage, einem Katheter zur Nephrostomie-Drainage, einem Katheter zur nasalen Pankreasdrainage und einem Katheter zur nasalen biliären Drainage bestehenden Gruppe ausgewählt ist.
- Katheter nach Anspruch 1, worin der mindestens eine pharmakologische Wirkstoff einen Alphablocker oder einem Kalziumkanalblocker umfasst.
- Katheter nach Anspruch 1, worin der mindestens eine pharmakologische Wirkstoff aus der aus einem Thrombin-Inhibitor, einem antithrombogenen Mittel, und einem Gemisch aus einem Thrombin-Inhibitor und einem antithrombogenen Mittel bestehenden Gruppe ausgewählt ist.
- Katheter nach Anspruch 1, worin der mindestens eine pharmakologische Wirkstoff aus der aus einem proliferationshemmenden Mittel, einem chemotherapeutischen Antikrebsmittel, einem antiviralen Mittel, einem antimikrobiellen Mittel, einem Analgetikum, einem Narkosemittel, einem antiphlogistischen Mittel und einem Verkrustungen verhindernden Mittel bestehenden Gruppe ausgewählt ist.
- Katheter nach Anspruch 1, worin der mindestens eine pharmakologische Wirkstoff aus der aus Rifampin, Minocyclin und einem Gemisch aus Rifampin und Minocyclin bestehenden Gruppe ausgewählt ist.
- Katheter nach Anspruch 1, worin der mindestens eine pharmakologische Wirkstoff aus der aus Urokinase, Streptokinase, einem Gewebeplasminogenaktivator, Heparin, kovalentem Heparin, Hirudin, Hirulog, Argatroban, D-Phenylalanyl-L-poly-L-arginyl-chlormethylketon, einem Thrombozytenaggregationshemmer und Gemischen davon bestehenden Gruppe ausgewählt ist.
- Katheter nach Anspruch 1, worin der mindestens eine pharmakologische Wirkstoff ein antimikrobielles Mittel umfasst.
- Katheter nach Anspruch 1, worin der mindestens eine pharmakologische Wirkstoff Bupivacain ist.
- Katheter nach Anspruch 1, worin der Katheter ein nicht-metallische Vorrichtung ist.
- Katheter nach Anspruch 1, ferner einen an einem Ende des Katheters angeordneten Abgabepunkt umfassend, worin der Abgabepunkt die Abgabe des mindestens einen pharmakologischen Wirkstoffs in den Schaumstoff gestattet.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US11/638,141 US20070161967A1 (en) | 1996-06-04 | 2006-12-13 | Implantable medical device with pharmacologically active ingredient |
PCT/US2007/087064 WO2008076706A2 (en) | 2006-12-13 | 2007-12-11 | Implantable medical device with pharmocologically active ingredient |
Publications (2)
Publication Number | Publication Date |
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EP2101836A2 EP2101836A2 (de) | 2009-09-23 |
EP2101836B1 true EP2101836B1 (de) | 2014-11-26 |
Family
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EP07855068.8A Active EP2101836B1 (de) | 2006-12-13 | 2007-12-11 | Implantierbares medizinprodukt mit einem pharmakologischen wirkstoff. |
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US (1) | US20070161967A1 (de) |
EP (1) | EP2101836B1 (de) |
WO (1) | WO2008076706A2 (de) |
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US8425459B2 (en) | 2006-11-20 | 2013-04-23 | Lutonix, Inc. | Medical device rapid drug releasing coatings comprising a therapeutic agent and a contrast agent |
US8414909B2 (en) | 2006-11-20 | 2013-04-09 | Lutonix, Inc. | Drug releasing coatings for medical devices |
US8414525B2 (en) | 2006-11-20 | 2013-04-09 | Lutonix, Inc. | Drug releasing coatings for medical devices |
US8414526B2 (en) | 2006-11-20 | 2013-04-09 | Lutonix, Inc. | Medical device rapid drug releasing coatings comprising oils, fatty acids, and/or lipids |
US9700704B2 (en) | 2006-11-20 | 2017-07-11 | Lutonix, Inc. | Drug releasing coatings for balloon catheters |
US8414910B2 (en) | 2006-11-20 | 2013-04-09 | Lutonix, Inc. | Drug releasing coatings for medical devices |
US9737640B2 (en) | 2006-11-20 | 2017-08-22 | Lutonix, Inc. | Drug releasing coatings for medical devices |
US20080276935A1 (en) | 2006-11-20 | 2008-11-13 | Lixiao Wang | Treatment of asthma and chronic obstructive pulmonary disease with anti-proliferate and anti-inflammatory drugs |
US8932345B2 (en) | 2007-02-07 | 2015-01-13 | Cook Medical Technologies Llc | Medical device coatings for releasing a therapeutic agent at multiple rates |
CA2687284A1 (en) * | 2007-03-20 | 2008-09-25 | Boston Scientific Limited | Urological medical devices for release of therapeutic agents |
AU2008293471B2 (en) * | 2007-08-31 | 2013-10-24 | Cook Medical Technologies Llc | Medical implant having improved drug eluting features |
US20110160844A1 (en) * | 2008-01-18 | 2011-06-30 | Med Institute Inc. | Intravascular device attachment system having biological material |
WO2009154834A2 (en) * | 2008-03-27 | 2009-12-23 | Boston Scientific Scimed, Inc. | Ureteral stents for release of urologically beneficial agents |
CN102946936B (zh) * | 2010-03-30 | 2016-05-04 | 火花医学研究有限公司 | 药物释放医用导管、管和装置 |
US9033956B2 (en) * | 2011-09-06 | 2015-05-19 | Cook Medical Technologies Llc | Electrically charged medical device |
DE102011119160A1 (de) * | 2011-11-22 | 2013-05-23 | Largentec Gmbh | Vorrichtung zum Verhindern und/oder Behandeln von Harnwegsinfektionen |
ES2901800T3 (es) | 2013-02-28 | 2022-03-23 | Boston Scient Scimed Inc | Dispositivos médicos para uso en el tracto biliar y/o pancreático |
EP3035991B1 (de) * | 2013-08-19 | 2020-07-08 | TARIS Biomedical LLC | Mehrteilige wirkstofffreisetzungsvorrichtungen |
HUE052701T2 (hu) | 2014-05-12 | 2021-05-28 | Taris Biomedical Llc | Gyógyszeradagoló eszközök |
US20180126129A1 (en) * | 2014-07-21 | 2018-05-10 | Stentorium Ltd | Implantable Stent |
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US11045589B2 (en) | 2017-09-22 | 2021-06-29 | Becton, Dickinson And Company | 4% trisodium citrate solution for use as a catheter lock solution |
CN108325045B (zh) * | 2018-02-09 | 2024-04-30 | 大连大学 | 多功能鼻胆引流管 |
JP7348292B2 (ja) | 2019-01-07 | 2023-09-20 | ボストン サイエンティフィック サイムド,インコーポレイテッド | 移動防止機構付ステント |
US11207453B2 (en) | 2019-05-24 | 2021-12-28 | Baxter International Inc. | Drug diffusing peritoneal dialysis catheter |
CN116801841A (zh) | 2020-12-02 | 2023-09-22 | 波士顿科学国际有限公司 | 具有改进的部署特性的支架 |
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DE10024752A1 (de) * | 2000-05-16 | 2001-11-29 | Ben Pfeifer | Mittel und Vorrichtung zur Behandlung von Prostata-Erkrankungen |
DE10059818A1 (de) * | 2000-12-01 | 2002-06-13 | Clariant Gmbh | Dekorative kosmetische und dermatologische Mittel |
US7862552B2 (en) * | 2005-05-09 | 2011-01-04 | Boston Scientific Scimed, Inc. | Medical devices for treating urological and uterine conditions |
-
2006
- 2006-12-13 US US11/638,141 patent/US20070161967A1/en not_active Abandoned
-
2007
- 2007-12-11 WO PCT/US2007/087064 patent/WO2008076706A2/en active Application Filing
- 2007-12-11 EP EP07855068.8A patent/EP2101836B1/de active Active
Also Published As
Publication number | Publication date |
---|---|
US20070161967A1 (en) | 2007-07-12 |
WO2008076706A3 (en) | 2009-06-04 |
WO2008076706A2 (en) | 2008-06-26 |
EP2101836A2 (de) | 2009-09-23 |
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